16 Alkaloids By H. F. HODSON The Wellcome Research Laboratories Beckenham Kent BR3 3BS 1 Introduction For a comprehensive survey of the whole alkaloid field the reader is again referred to the latest volume’ of the Specialist Periodical Reports on Alkaloids which covers the period from July 1971 to June 1972. Biosynthetic aspects are also treated in the companion volume’ on biosynthesis which following the pattern of last year includes a tabular survey of all tracer incorporations into alkaloids reported during 1972. 2 Pyridine and Imidazole Alkaloids A fungal alkaloid (1 ;or enantiomer) from Rhizoctonia legminicola is a unique example of a natural 1-pyrindene ; like slaframine (2) previously isolated from the same source it is biosynthesized via pipecolic acid from lysine.3 It has been noted that the structures (3) and (4) previously assigned4 to iso- longistrobine and dehydroisolongistrobine,are inconsistent with the published spectroscopic data.Syntheses have confirmed the revised structures (5) for isolongistrobine and (6) for dehydroisolongistrobine. ‘The Alkaloids’ ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London 1973 Vol. 3. ‘Biosynthesis’ ed. T. A. Geissman (Specialist Periodical Reports) The Chemical Society London 1973 Vol. 2. F. P. Guengerich S. J. Di Mari and H. P. Broquist J.Amer. Chem. SOC.,1973,95,2055. Ann. Reports (B) 1969 66 471. M. A. Wuonola and R. B. Woodward J. Amer. Chem. SOC.,1973.95 284. 529 5 30 H. F. Hodson 0 Me I (5) X = H,OH (3) (4) (6) X = 0 3 Acridone Alkaloids Nearly thirty acridone alkaloids have been isolated to date all from plants of the Rutaceae family.Among new examples this year are the novel ether-linked bis-acridones ataline (7) and atalantine (8) from Atalantia ceylanica;6 the C-5'-C-6 position of the ether link was not rigorously established but is bio- genetically reasonable. Mono-acridone alkaloids were also isolated from the same species. * 4 Isoquinoline Alkaloids During recent years much of the interesting work in this area has been concerned with the in uiuo and in uitro transformations of benzylisoquinolines and phenyl- ethylisoq~inolines~ into the derived systems such as aporphines morphinandie- nones erythrina alkaloids and their homologues.The key step in these trans- formations is an intramolecular aryl-aryl coupling reaction and for the bio- synthetic routes the evidence suggests oxidative coupling of appropriate di- phenolic precursors. Much ofthe in uitro work has therefore involved the reaction of such precursors with a variety of one-electron oxidizing agents with coupling of the resultant diphenoxyl radical." The current year sees two significant M. A. Wuonola and R. B. Woodward J. Amer. Chem. SOC.,1973.95 5098. ' A. W. Fraser and J. R. Lewis J.C.S. Chem. Comm. 1973 615. A. W. Fraser and J. R. Lewis J.C.S. Perkin I 1973 1173. T. Kametani in 'The Alkaloids' Academic Press New York 1973 Vol. 14 p. 265. lo T. Kametani and K. Fukumoto Synthesis 1972 657. Alkaloids 531 departures in this area of intramolecular oxidative coupling both of which could have biogenetic implications.The first of these" is illustrated in a synthesis (Scheme 1) of the colchicine precursor (f)-0-methylandrocymbine (10) by a route which involves a two-electron oxidation with thallium(Ir1) trifluoroacetate of a mono-phenolic pre-cursor (9) the novel use of the N-BH protecting group is noteworthy. Previous attempts to prepare (10) by oxidative coupling of the appropriate diphenol had failed. N Me HO ' HO OMe OMe .. ... II 111 J OMe OMe Reagents i BH in THF-CHCl,; ii TTFA in CH,Cl,; iii Na,CO,-MeOH reflux. Scheme 1 Another example of oxidative coupling of a monophenolic substrate is pro- vided by the conversion" of the fully aromatic isoquinoline (11) into the quinonoid oxoaporphine (13); this transformation is mediated by a variety of reagents including both recognized one-electron and two-electron oxidants in yields of 10-60%.Alkaloid (13)was also isolated from a Pschorr cyclization of the diazonium salt (12); presumably the expected product (14) suffers im- mediate aerial oxidation to the fully conjugated (13).13 'I M. A. Schwarz B. F. Rose and B. Vishnuvajjala J. Amer. Chem. SOC.,1973,95 612. l2 S. M. Kupchan and A. J. Liepa J. Amer. Chern. SOC.,1973,95,4062. See also M. P. Cava I. Noguchi and K. T. Buck,J. Org. Chem. 1973 13,2394. 5 32 H. F. Hodson I I OMe OMe OMe (11) R' = R2 = H (14) (12) R' = Ac R2 = N,+ The second departure' involves the intramolecular coupling of non-phenolic benzylisoquinolines mediated by vanadium oxytrichloride.With this reagent in the presence of trifluoroacetic acid (-t)-N-formylnorlaudanosine (15) was converted into a mixture of the aporphine N-formylnorglaucine (16) and the spirodienone (17) the structure of which was established by X-ray analysis. Under the same conditions (+)-laudanosine (18) gave (rt)-glaucine (19) in 43% yield. A likely mechanism for the formation of (17) involves the oxidative demethylation. Hydride reduction of the dimethylacetal from (17) gave 0-methylerybidine (21) with the dibenzazonine structure established as an in uitro and in uivo precursor of the Erythrina alkaloids. '9~~0 MeoFR formation [ct (15) path b] of (20) followed by rearrangement (20; arrows) and \ Me0 M b...Y .;.-' /.o R Me0 \ e ' ' ' Me0 Me0 Me0 OMe OMe OMe (15) R = CHO (18) R = Me (16) R = CHO (19) R = Me (17) OMe OMe M e< Me03 \-Me0 ' 1 NCHO M e O k p'NMe Me0 OMe OMe 0 (20) (21) (22) l4 S.M. Kupchan A. J. Liepa V. Kameswaran and R. F. Bryan J. Amer. Chem. SOC. 1973 95 6862. Alkaloids 533 The only previous example of the coupling of non-phenolic substrates is provided by the anodic oxidation of (f)-laudanosine (18) first reportedI5 two years ago and now described in detail for (18) and several analogues;16 very similar results under somewhat simpler conditions are independently reported.” In contrast to the chemical oxidations discussed above [cf.(18) routes a and b] the electroxidative cyclizations follow route c exclusively to give high yields (up to 86 %) of products e.g.(22) from (18) with the morphinandienone skeleton. The prohomoerythrinadienone (23) prepared for the first time by a standard phenol oxidation procedure readily undergoes acid-catalysed dienone-phenol rearrangement to the homoaporphine (24) in 75% yield.I8 This is in striking contrast to the behaviour of the corresponding proerythrinadienone system cf. (25) which has never been rearranged to an aporphine presumably because of steric constraints ;’ the rearrangement normally takes a different course to give a dienone of type (17) ;cf. (20)-+(17). This year however the aporphine (27) has been obtained2’ from the dienol(26) but in less than 1 % yield the major product being an enone of skeletal type (17).Me0 Ho~NcOCFI HO Q OMe OH Ann. Reports (B) 1971,68 497. l6 L. L. Miller F. R. Stermitz and J. R. Falck J. Amer. Chem. Soc. 1973 95 2652. ” E. Kotani and S. Tobinga Tetrahedron Letters 1973 4759. J. P. Marino and J. M. Samanen Tetrahedron Letters 1973 4553. ‘ M. Shamma in ref. 1 p. 136 and T. Kametani K. Takahashi T. Honda M. Ihara and K. Fukumoto Chem. and Pharm. Bull. (Japan) 1972 20 1973. ’O T. Kametani K. Takahashi K. Ogasawara and K. Fukumoto Chem. and Pharm. Bull. (Japan) 1973 21 662. 5 34 H. F. Hodson Me0 \ xpo2Et Meopco2Et Me0 Me0 ' OMe OMe (25) X = 0 (26) X = H,OH (27) An amorphous green base nandazurine (29) has the same zwitterionic meso- meric structure2' as the hitherto unique alkaloid corunnine (28).Both alkaloids have been synthesized22 by a route which employs a photocyclization to complete the aporphine system; corunnine has also been prepared via a conventional Pschorr ring-cl~sure.~~ R R (28) R = Me0 (29) RR = OCHZO A new route24 to protoberberine alkaloids is exemplified by a synthesis of (+)-xylopinine (32) in which the key step is photocyclization of the enamide (30) to give (31)accompanied by its dehydro-derivative. Me0 OMe OMe (30) (31) X = 0 (32) X = H l' J. Kunitomo M. Ju-Ichi Y. Yoshikawa and H. Chikamatsu Experientia 1973 29 518. l2 S. M. Kupchan and P. F. O'Brien J.C.S. Chem.Comm. 1973,915. 23 I. Ribas J. SBa and L. Castedo Tetrahedron Letters 1973 3617. 24 I. Ninomiya and T. Naito J.C.S. Chem. Comm. 1973 137. Alkaloids 535 Another synthesis of the protoberberine system makes use of the recently described’ thermolysis of benzocyclobutenes to o-quinodimethide intermediates. Thus in bromobenzene at 150-16OoC (33) and (34) gave about 90% yield of the protoberberinium salts (35)26and (36),’’respectively;the extra unsaturation was presumably introduced oxidatively during work-up. Me0 OMe OMe (33) R = Me (35) R = Me (34)R = PhCHz (36) R = PhCH A quinodimethide intermediate is also probably implicated in a photochemical synthesis ** of the spiroisoquinoline (38). Irradiation of a basic solution of the oxotetrahydroberberinium salt (37) gave (38) in 45 % yield presumably /I+ Me q Q 0 /-o/ OMe 1 (37) by the steps indicated.The reverse process has also been effected photo- ~hemically;~~ irradiation of (39) in neutral solution gave the berberinium salt (35). ’’ Ann. Reports (B) 1971 68 494. 26 T. Kametani K. Ogasawara and T. Takahashi Tetrahedron 1973 29 73; J.C.S. Chem. Comm. 1972,675. ” T. Kametani Y. Hirai F. Satoh K. Ogasawara and K. Fukumoto Chem. and Pharm. Bull. (Japan) 1973 21 907. 28 B. Nalliah R. H. F. Manske R. Rodrigo and D. B. MacLean Tetrahedron Letters 1973 2795. *’ H. hie K. Akagi S. Tani K. Yabusaki and H. Yamane Chem. and Pharm. Bull. (Japan) 1973 21 855. 536 H. F. Hodson Three new alkaloids3' from Corydalis incisa corydalic acid methyl ester (40),3 corydamine (41),3zand N-f~rmylcorydamine,~~ are 3-arylisoquinolines and formally of a new structural type although their biogenetic affinities with protoberberine alkaloids e.g.(42) which occurs in the same species,30 are obvious ;note that the isoquinoline ring in (40)and (41)is not the biosynthetically original isoquinoline nucleus. O'Me OMe (40) Although it has generally been presumed that alkaloids are end-products of plant metabolism during recent years there have been sporadic reports33 indicating that in at least some cases they may play an important dynamic functional role in plant metabolic processes. Such a report this year is concerned with the fate of morphine (43)in Pupaver sornniferurn where it is shown to be converted irreversibly into normorphine (a), now identified as a natural alkaloid ; normorphine is in turn degraded to non-alkaloidal metabolite^.^^ Morphine is biosynthesized via thebaine (45)and codeine (46)and it is now clear that throughout the lifecycle of the plant there is a high rate of turnover in the sequence from thebaine to normorphine and beyond a sequence involving successive demethylation steps.This leads to the hypothesis34 that the morphine alkaloids in this sequence are acting as specific methylating agents. 30 G. Nonaka H. Okabe I. Nishioka and N. Takao Yakugaku Zasshi 1973,93 87. 3' G. Nonaka Y. Kodera and I. Nishioka Chem. and Pharm. Bull. (Japan) 1973 21 1020. 32 G. Nonaka and I. Nishioka Chem. and Pharm.Buff.(Japan) 1973,21 1410. 33 E. Leete in ref. 2 p. 1 1 1. 34 R. J. Miller C. Jolles and H. Rapoport Phyrochemistry 1973 12 597. Alkaloids 537 R'O NR2 (43) R' = H R2 = Me (45) (44) R' = R2 = H (46) R' = R2 = Me Significant findings of another kind are also associated with morphine. For some time pharmacologists have been building up a compelling body of evidence for the existence of a specific opiate receptor which recognizes morphine and related opiates and also morphine antagonists [e.g. (-)-naloxone]. Now from various mammalian species there have been isolated membrane fractions of nervous tissue which selectively form complexes with opiate drugs at very low concentrations (down to 1 x moll-for naloxone).The binding is highly stereospecific and correlates well with known pharmacological potencies. These res~lts~~-~~ should give greater insight into the mode of action of opiate drugs. A synthesis of cephalotaxine (47)reported4' last year incorporated a cyclization of the anion (48; X = C1 Br or I) to (49) under benzyne-forming conditions; yields were less than 10%. A reinvestigation4' of this step has shown that the conversion can be effected most efficiently through a photo-stimulated intra- molecular SR,l reaction;42 irradiation of (48; X = I) in liquid ammonia in the presence of potassium t-butoxide produced an astonishing 94 % of (49). " c.B. Pert and S. H. Snyder Science 1973 179 1011; Proc. Nat. Acad. Sci. U.S.A. 1973,70 2243. 36 L.Terenius Acta Pharmacol. Toxicol. 1973 32 317. '' E. J. Simon J. M. Hiller and I. Edelman Proc. Nar. Acad. Sci.U.S.A.,1973,70 1947. " M. J. Kuhar C. B. Pert and S. H. Snyder Nature 1973 245 447. 39 C. B. Pert G. Pasternak and S. H. Snyder Science 1973 182 1359. 40 Ann. Reports (B) 1972 69 494. 4' M. F. Semmelhack R.D. Stauffer and T. D. Rogerson Tetrahedron Letters 1973 4519. 42 R.A. Rossi and J. F. Bunnet J. Org. Chem. 1973. 38 1407. 538 H. F. Hodson 5 Amaryllidaceae Alkaloids Aryl-aryl coupling of non-phenolic substrates by electro-oxidative methods employed so effectively in the benzylisoquinoline series has now been applied to the synthesis43 of (f)-oxocrinine (52) and (+)-oxomaritidine (55) with yields of 60% in the coupling reactions (50) to (51) and (53) to (54).The well-trodden phenol oxidation procedure e.g. (56) to (57) has been effected in 35% yield with yet another reagent the iron-DMF complex [Fe(DMF),Cl,] [FeC14].44 A synthesis45 of the lactonic alkaloid (f)-clivonine (60) commenced with a cycloaddition reaction to give (58); conversion to (59) was followed by two oxidative steps as indicated. COCF (51) R'R' = CH, (50)R'R2 = CH,,R3 = Me / (54)R' = R2 = Me (53) R' = R2 = R3 = Me (57)R' = Me R2 = H (56)R' = Me,R2 = R3 = H R20 R1o&o (52) R'R~= CH (55) R' = R2 = Me 6 Terpenoid Indole Alkaloids Strychnos angustijlora an Asian species has furnished the three closely related yellow angustoline (61) angustine (62) and angustidine (63).further4' examples of pyridines closely related to the seco-iridoid precursor(s) of the many indole alkaloids so far isolated from this genus. The new bases were obtained in an ammonia-free work-up and are not therefore artefacts. The assigned structures followed mainly from spectroscopic data and in two cases have been confirmed by synthesis. In one synthetic study48 the aglycone (64) from dihydrovincoside lactam was converted with aqueous ammonia into an unstable product formulated as (65) ; 43 E. Kotani N. Takeuchi and S. Tobinga J.C.S. Chem. Comm. 1973 550. 44 E. Kotani N. Takeuchi and S. Tobinga Tetrahedron Letters 1973 2735. 45 H. hie Y. Nagai K. Tamoto and H. Tanaka J.C.S. Chem. Comm. 1973 302. 46 T. Y. Au H. T. Cheung and S. Sternhell J.C.S.Perkin I 1973 13. 47 cf. Ann. Reports (B) 1972 69 498. ** R.T. Brown A. A. Charaiambides and H. T. Cheung Tetrahedron Letters 1973,4837. A lkaloids 539 0 (60) Reagents i Os0,-Et,O; ii sepn. of isomers; iii Mn0,-CHCI dehydration and oxidation then furnished dihydroangustine [cf (62)] identical with the reduction product of angustine. The other ~ynthesis:~ of angustidine (63) exploited the enamide photo- cyclization first employed in a synthesis of (f)-crinane full details of which have NH Et * OH (64) (65) 49 I. Ninomiya. H. Takasugi and T. Naito J.C.S. Chem. Comm. 1973 732. 540 H. F. Hodson appeared this year.50 Irradiation of (66) gave two isomeric bases one of which (20%) was identical with natural (63); the other base was the product of the alternative cyclization on to the pyridine 6-position.~ T ! N J Ho2cPH \o /6 Me0,C Some years ago the structure (67) was assigned to the naturally occurring antiviral compound elenolic acid. On spectroscopic grounds this is now re- formulated'' as (68) which was confirmed by a total synthesis of the racemic methyl ester.52 The depicted (68) absolute stereochemistry was established" by a stereorational conversion (Scheme 2) into (-)-ajmalicine (69). H ,,Me H i-iii T HO,C CHO ee H-' H MeOzC'bo Reagents i esterification; ii tryptamine; iii NaBH,; iv POC1,-PhH reflux; v NaBH Scheme 2 50 I. Ninomiya T. Naito and T. Kiguchi J.C.S. Perkin I 1973 2261. 5L F. A. MacKellar R. C. Kelley E.E. van Tamelen and C. Dorschel J. Amer. Chern. SOC.,1973 95 7155. 52 R. C. Kelley and I. Schletter J. Amer. Chem. SOC.,1973 95 7156. Alkaloids 541 Adina rubescens the source of so many interesting tryptophan-derived indole alkaloids (i.e. those retaining the carboxylate function) has provided still two more both with unique structural features but both clearly very close to a precursor such as 5-carboxystrictosidine (70).53One of these alkaloids de- soxycordifoline lactam (7 1) incorporates an unprecedented seven-membered indole lactam; it was isolated as the tetra-acetate and could be converted into the known deoxycordifoline (70; ring c aromatic). Rubenine (72) the second alkaloid has a unique N(b)-C-18 bond in a seven-membered ring; most of the structural features were recognized in a detailed n.m.r.and mass spectral study of (72) and its derivative^.^^ H Me0,C bo Me Q o0 (72) (73) R = C0,Me (74) R = H A tryptophan-derived structure (73) is also proposed55 for cannagunine B from the cranberry Vucciniurn oxycoccus. This structural assignment however relies heavily on an earlier assignments6 of the novel structure (74) to canna- gunine from the same source and the evidence as then presented for the latter structure was not wholly convincing; the U.V. maximum for example was reported at 338 nm ! The dehydroyohimbane system (76) has been prepared in 70% yield by thermolysis of the appropriate benzocyclobutene (75),5 ' a route analogous to that described on p. 535 for the protoberberine system." R. T. Brown and S. B. Fraser Tetrahedron Letters 1973 841. s4 R. T. Brown and A. A. Charalambides J.C.S. Chem. Comm. 1973 765. 55 K. Jankowski Experientia 1973 29 519. 56 K. Jankowski J. Boudreau and I. Jankowska Experientia 1971 27 1141. 57 T. Kametani M. Kajiwara and K. Fukumoto Chem. and Ind. 1973 1165. 542 H. F. Hodson OMe OMe (75) Four years ago it was shown that in Strychnos nux vornica tryptophan and geraniol were as expected both incorporated into strychnine (82) the additional two-carbon bridge being provided by acetate. In these short-term hydroponic experiments it was not possible to demonstrate the incorporation of more advanced intermediates such as geissoschizine(78) Wieland-Gumlich aldehyde (79) or diaboline (80).Now prolonged feeding experiments have shown that both geissoschizine and W-G aldehyde but not diaboline are significantly incorporated into ~trychnine.~~ H‘ Me0,C 3 I OH (79) R = H (78) (80) R = AC In two short-term experiments after feeding with labelled tryptamine or with acetate modified work-up furnished a new base-soluble (amphoteric) alkaloid which could be converted into strychnine on warming with dilute acid. This alkaloid which would be converted into strychnine during normal work-up was named prestrychnine and was plausibly formulated as (81).58 58 S. I. Heimbergerand A. I. Scott J.C.S. Chem. Comm. 1973 217. Alkaloids 543 The interesting but biosynthetically unexceptional structure (83) has been assigned to geissovelline a new alkaloid from Geissospermum uellosii by a combination of classical degradation and spectroscopic studies.59 The U.V. spectrum in neutral solution exhibits both N-acylindoline and afl-unsaturated ketone chromophores. In acidic solution the latter disappears leaving a pure N-acyldialkoxyindoline spectrum ; the transannular interaction between the amino and carbonyl functions ensures that protonation occurs on the oxygen to give (84). {fie HH Ac (84) (83) The novel lactam rhazinalam (86) described last year has now been neatly synthesized (Scheme 3) by a route6' in which the full carbon-nitrogen skeleton was incorporated into the pyrrole-lactam (85) produced by an N-alkylation of the appropriately substituted pyrrole.The methoxycarbonyl function served to direct the cyclization of (85) and was removed in the terminal stages to give racemic (86). The depicted (86) absolute stereochemistry followed from a partial synthesis6* by oxidation of ( k)-1,2-dehydroaspidospermidineof known con- figuration. % Il-v 3 &! CO,Me N u I CO,H H Reagents i AlC1,-MeNO,; ii H,-Adams catalyst; iii DCC-DMF; iv NaOH-H,O-MeOH; v decarboxyiation Scheme 3 I3C N.m.r. spectroscopy has played a predominant role in the structural elucidation of several alkaloids newly isolated this year. These include the s9 R. E. Moore and H. Rapoport J. Org. Chem. 1973,38 215. 'O A. H. Ratcliffe G. F. Smith and G. N. Smith Terrahedrorl Letrers 1973 5179. 544 H.F.Hodson bis-indole alkaloid criophylline (87),61 from Crioceras dipladenijlorus and the tabersonine-like vandrikidine (88) vandrikine (89),and hazuntinine (90). These last three bases were examined as part ofa detailed analysis,62 usinga combination H I C0,Me H (89) of decoupling techniques of a number of Aspidosperma bases. Further63a information is now provided63b on the existence of two distinct stereochemical series within this family a consequence of the involvement of a common achiral biosynthetic precursor such as (92). The new work includes a number of 0.r.d. comparisons and provides another absolute standard by an X-ray analysis of natural (*)-coronaridhe (91) the enantiomer of the natural coronardine of last year's63a study.There is still no resolution of the controversy surrounding the claimed inter- conversion in refluxing acetic acid of indole alkaloids of the coryanthe aspido- 61 A. Cave J. Bruneton A. Ahond A. M. Bui H.-P. Husson. C. Kan G. Lucacs and P. Potier Tetrahedron Letters 1973 508 1. 62 E. Wenkert D. W. Cochran E. W. Hagaman F. M. Scheii N. Neuss A. S. Katner P. Potier C. Kan M. Plat M. Koch H. Mehri J. Poisson N. Kunesch and Y. Rolland J. Amer. Chem. SOC.,1973 95 4990. 63 (a) Ann. Reporrs (B) 1972 69 501 ;(b)J. P. Kutney K. Fuji A. M. Treasurywala F. Fayos J. Clardy A. I. Scott and C. C. Wei J. Amer. Chem. Soc. 1973 95 5407 Alkaloids 545 sperma and iboga skeletal types.64 A note6’ comments on the work reported last year by Scott and Wei.64 It emphasizes the fact that although this work showed that interconversions of the three skeletal types can be achieved in vitro the transformations were effected under specific conditions quite remote from those originally described and with yields very much lower than claimed earlier.It was not therefore a vindication of the earlier work as described,66 work which others have been unable to duplicate and for which full experimental details have still not been published. 7 Quinoline Alkaloids Biogenetically Derived from Indoles The interest in camptothecin (93b),67 particularly in the total synthesis of the alkaloid and of analogues has continued unabated although it now appears that the initial high hopes for its utility as an anticancer agent have dwindled.Despite the fact that six total syntheses had been reported by the end of 1972 new ones reported this year are again sufficiently different in approach to be worthy of comment. One synthesis68 depended on the prior assembly of the complete CDE ring system in (94) ; in a Friedlander quinoline synthesis with anthranilaldehyde this gave ( f)-deoxyde-ethylcamptothecin (93a) which had previously6’ been converted into ( +)-camptothecin. (93) a; R’= RZ= H (94) b; R’= OH R2 = Et 64 Ann. Reports (B) 1972 69 501. 65 R. T. Brown G. F. Smith J. Poisson and N. Kunesch J. Amer. Chem. Soc. 1973 95 5778. 66 A. A. Qureshi and A. I. Scott Chem. Comm. 1968 947. 67 A. G.Schultz Chem. Rec. 1973 73.385. 68 M. Shamma D. A. Smithers and V. St.Georgiev Tetrahedrori 1973 29 1949. 69 Ann. Reports (B) 1972 69 503. 546 H. F. Hodson Alkaloid (93a) also featured in another synthe~is,’~ which commenced with the intact ABC ring system in (96) ;successive acylation and Michael reactions gave the completely functionalized intermediate (95) in which the elements of the pentacyclic lactone are readily recognized. A third synthesis7’ arrived at the tetracyclic ester (101) which had been converted into (+)-camptothecin in one of the early routes.69 The key inter- mediate (99) was prepared from (98) via (97) the latter being obtained from furfural in six steps. Although (99) has the full carbon skeleton of deoxyde- ethylcamptothecin (93) attempts at a direct conversion were fruitless ;alkaline hydrolysis of (99) in fact produced (100) via ring-opening and deformylation.Compound (100) was therefore converted into (101) from which following the earlier work the ‘lost’ carbon could be reintroduced by a formylation step. /!. (101) (100) (99) ’O A. I. Meyers R. L. Nolen E. W. Collington T. A. Narwid and R. C. Strickland J. Org. Chem. 1973 38 1974. ” A. S. Kende T. J. Bentley R. W. Draper J. K. Jenkins M. Joyeux and I. Kubo Tetrahedron Letters 1973 1309. A lkaloids 547 8 TerpenoidBases The common carbon skeleton of the complex C22 and C30 Daphniphyllum alkaloids suggests a mevalonoid origin and feeding experiments have now ~onfirmed’~ that six molecules of mevalonic acid are incorporated into the C30 alkaloids daphniphylline (102) and codaphniphylline (103) ; squalene was also incorporated to the extent of 0.008% and a plausible origin from a squalene-like intermediate is suggested.It is likely73 that the CZ2bases such as daphnilactone B (104) are derived from a C, precursor by oxidative loss of an eight-carbon unit. Me (102) R = OAc (103) R = H Me (104) 9 Miscellaneous Alkaloids Three alkaloid^'^ (105) (106) and (107) from the leaves of Homliurn pronyense are closely related to the principal alkaloid homaline (108) the structure of \NAc / R2 R’ (105) R’= [CH,],Me R2 = [CH2],Me (106) R’= [CH,],Me R2= CH,CH(OH)[CH i (107) R’= Ph R2 = CH,CH(OH)[CH,],Me (108) R’= RZ= Ph 0 H I Ph NH[CH2],-N[CH2],-NH 72 K. T. Suzuki S. Okuda H.Niwa M. Toda Y.Hirata and S. Yamamura Tetrahedron Letters 1973 799. ” H. Niwa Y. Hirata K. T. Suzuki and S. Yamamura Tetrahedron Letters 1973 2129. 74 M. Pais R. Sarfati F.-X. Jarreau and R. Goutarel Tetrahedron 1973 29 1001. 548 H. F. Hodson which was confirmed by synthesis two years ago. These bases are presumably biogenetically derived from spermine and various orb-unsaturated carboxylic acids and it is interesting to note that the alkaloid maytenine first isolated 35 years ago has now been identified’’? ’‘ as di-trans-cinnamoylspermidine (109). Another example of this increasing group of spermine- and spermidine- derived alkaloids is the macrocyclic alkaloid chaenorine (1 ’* G. Englert K. Klinga Raymond-Hamet E. Schlittler and W.Vetter Helv. Chim. Acta 1973 56 474. 76 E. Schlittler U. Spitaler and N. Weber Helv. Chim. Acra 1973 56 1097. ” H. 0. Bernhard I. Kompis S. Johne D. Groger M. Hesse and H. Schmid Helv. Chim. Acta 1973 56 1266.